This invention relates to a process for the synthesis of N-acyl-2-amino-4-alkoxy-5-nitrobenzoic acids by the oxidation of N-(5-alkoxy-2-methyl-4-nitrophenyl)acetamides using potassium permanganate in aqueous solvent mixtures.
Potassium permanganate is a widely used reagent for the oxidation of benzylic carbon atoms to the corresponding carboxylic acid. However, oxidations do not always work well for substrates having limited water solubility and furthermore, potassium permanganate has limited solubility in organic solvents. The problem with insolubility has been addressed to some extent by the use of biphasic conditions employing water and either benzene or a hydrocarbon solvent as the organic phase, or, alternatively by using a phase transfer catalyst. Unfortunately, many organic compounds or substrates have poor solubility in either water or hydrocarbon solvents. The limited contact between the oxidant and the substrate results in long reaction times, poor yields and the formation of contaminates which make purification difficult. Further, many typical organic solvents cannot be used as a co-solvent with potassium permanganate because being such a potent oxidant, the organic solvents are themselves oxidized, leading to diverse and complicated reaction mixtures. The use of a phase transfer catalyst can lead to further purification problems.
The N-acyl-2-amino-4-alkoxy-5-nitrobenzoic acids that are obtained according to the process of this invention are useful intermediates to produce 3-cyanoquinolines. The 3-cyano quinolines are used in the synthesis, as described in U.S. Pat. No. 6,002,008, the disclosure of which is hereby incorporated by reference in its entirety, of certain protein tyrosine kinase (PTK) inhibitors useful for the treatment of cancer. The toluidines that are required to produce the desired N-acyl-2-amino-4-alkoxy-5-nitrobenzoic acids have very poor solubility in water. The problem of poor water solubility contributes to incomplete reactions and variable yields when performing the oxidation in water alone with potassium permanganate as the oxidizing agent in the presence of magnesium sulfate. The accelerated decomposition of potassium permanganate, under aqueous conditions requires a very large excess of the oxidant resulting in large volumes of inorganic waste. Additionally, the low solubility of both the substrate and the oxidant in water contribute to the inefficiency of the total process by requiring high dilutions (>40:1).
It is also known that certain substrates, which include derivatives of toluidine such as N-(5-alkoxy-2-methyl-4-nitrophenyl)acetamides, can catalyze the decomposition of potassium permanganate. As mentioned above, solubility and decomposition problems contribute to the need for a large excess of potassium permanganate. Also, isolating and solving problems of potassium permanganate oxidations are difficult because of the subtleties of the equilibrium between the various oxidation states of manganese.
The N-(5-alkoxy-2-methyl-4-nitrophenyl)acetamides used as the oxidation substrates are prepared with acetic anhydride using conditions well described in the art (e.g., A. Ono in Chem. Ind.(London), 4, 130, 1982). As described, adding N-(5-alkoxy-2-methyl-4-nitrophenyl)acetamides as a solid to an aqueous mixture of the potassium permanganate and magnesium sulfate at about 80-90° C. followed by heating the reaction mixture to reflux for 1 hour further required adding additional potassium permanganate and magnesium sulfate as necessary at 30 minute intervals to fully oxidize the N-(5-alkoxy-2-methyl-4-nitrophenyl)acetamides. Typically, 4 to 5 equivalents of the oxidant are necessary under these conditions. The yield of the oxidation under totally aqueous conditions is however improved by adding the substrate as a hot slurry in water. However, the disadvantage to this procedure becomes apparent on larger scale when one needs to prepare the substrate as a hot slurry in water followed by adding the slurry to the aqueous potassium permanganate.
It is, therefore, an object of the present invention to provide a new process for the preparation of N-acyl-2-amino-4-alkoxy-5-nitrobenzoic acids which avoids the solubility problems associated with potassium permanganate in organic solvents and to additionally solve the problem of needing a large excess of potassium permanganate.
Thus, there is a need in the art for a process which overcomes the problems of solubility and the need for excess potassium permanganate when oxidizing, in particular, toluidines.
Those and other objects of the present invention will become more apparent from the detailed description thereof set forth below.